Piezoelectric Stimulation Research Articles

Alginate-based functionalized, remote, light-responsive hydrogel transducer for synergistic mild photo thermoelectric stimulation for tumor therapy

Photothermal therapy (PTT) is an effective cancer treatment that circumvents the resistance caused by chemotherapy drugs. Conventional PTT has a relatively high temperature, which is better able to kill tumor tissues, but it is also more damaging to normal tissues. Mild PTT avoids these high temperatures, but its corresponding killing ability becomes lower and enhances the heat resistance of cancer cells, causing tumor self-protection and reducing the therapeutic effect of PTT. Here, we reported a new, remotely stimulable, mild-temperature PTT combined with electrical stimulation-induced ionic interference therapy. We introduced MXenes into alginate based thermoresponsive PVA/P(NIPAm-co-SA) hydrogel (PPS) to formulate mechanically reliable hydrogel electrolyte-based supercapacitors as an ion homeostasis perturbator. The artificially controlled duration of near-infrared radiation modulates the PTT cycle temperature, which is controllably maintained at a little under 45 °C to reduce Hsp90 overexpression. Light-induced phase transitions in the hydrogel produce voltages that resemble low-intensity, alternating electric fields. Moreover, chronic piezoelectric stimulation can inhibit cancer cell proliferation by upregulating the expression of genes encoding Kir3.2 inwardly rectifying potassium channels, by interfering with Ca2+ homeostasis, and by affecting mitotic spindle organization during mitosis. In vivo and in vitro antitumor studies on the 4T1 model suggest that this functionalized, remote, light-responsive transducer is an effective and promising tool for the treatment of tumors.

Periosteum-bone inspired hierarchical scaffold with endogenous piezoelectricity for neuro-vascularized bone regeneration

The development of scaffolds for repairing critical-sized bone defects heavily relies on establishing a neuro-vascularized network for proper penetration of nerves and blood vessels. Despite significant advancements in using artificial bone-like scaffolds infused with various agents, challenges remain. Natural bone tissue consists of a porous bone matrix surrounded by a neuro-vascularized periosteum, with unique piezoelectric properties essential for bone growth. Drawing inspiration from this assembly, we developed a periosteum-bone-mimicking bilayer scaffold with piezoelectric properties for regeneration of critical-sized bone defects. The periosteum-like layer of this scaffold features a double network hydrogel composed of chelated alginate, gelatin methacrylate, and sintered whitlockite nanoparticles, emulating the viscoelastic and piezoelectric properties of the natural periosteum. The bone-like layer is composed of a porous structure of chitosan and bioactive hydroxyapatite created through a biomineralization process. Unlike conventional bone-like scaffolds, this bioinspired bilayer scaffold significantly enhances osteogenesis, angiogenesis, and neurogenesis combined with low-intensity pulsed ultrasound-assisted piezoelectric stimulation. Such a scheme enhances neuro-vascularized bone regeneration in vivo. The results suggest that the bilayer scaffold could serve as an effective self-powered electrical stimulator to expedite bone regeneration under dynamic physical stimulation.

Pressure-induced piezoelectric response for mitigating membrane fouling in surface water treatment: Insights from continuous operation and biofouling characterization

Organic fouling and biofouling represents a critical challenge encountered by the membrane-based water treatment process. Herein, a piezoelectric PVDF membrane (PEM), capable of generating electrical responses to hydraulic pressure stimuli, was synthesized and employed for mitigating the fouling in surface water treatment. The surface-hydrophobilized PEM demonstrated sensitive and enhanced underwater output performance in response to increasing transmembrane pressure (TMP) during constant-flux filtration, with signals reaching up to ∼800 mV at a TMP of ∼80 kPa. This in-situ piezoelectric response significantly reduced TMP growth in both short-term (1 h) and long-term (15 days) filtration trials, demonstrating a strong capability to mitigate membrane fouling. Moreover, continuous piezoelectric stimulation effectively inhibited microbial activity and the accumulation of extracellular polymeric substances (EPS) on PEM surface, surpassing the dominant electrokinetic repulsion mechanisms observed in short-term trials. Microbial community analysis suggests that this evolution is primarily due to the targeted impact of piezoelectric stimulation on microbial metabolic behavior. The piezoelectric-induced electrical microenvironment inhibited the growth of microbes associated with high EPS production while promoting the proliferation of electrically active microbes involved in biopolymer digestion. In addition, the PEM demonstrated enhanced permeate quality throughout the filtration process, with DOC and UV254 removal rates increasing from 11.7 % and 15.6 % initially to 28.6 % and 19.5 % by the 15th day, respectively. Given the performance and self-powered capability of PEM compared to current electrified antifouling methods that require an external power supply, these attributes are anticipated to hold practical significance in developing innovative and energy-efficient strategies for mitigating both organic fouling and biofouling.

Multimaterial Printing of Serpentine Microarchitectures with Synergistic Mechanical/Piezoelectric Stimulation for Enhanced Cardiac-Specific Functional Regeneration.

Recreating the natural heart's mechanical and electrical environment is crucial for engineering functional cardiac tissue and repairing infarcted myocardium in vivo. In this study, multimaterial-printed serpentine microarchitectures are presented with synergistic mechanical/piezoelectric stimulation, incorporating polycaprolactone (PCL) microfibers for mechanical support, polyvinylidene fluoride (PVDF) microfibers for piezoelectric stimulation, and magnetic PCL/Fe3O4 for controlled deformation via an external magnet. Rat cardiomyocytes in piezoelectric constructs, subjected to dynamic mechanical stimulation, exhibit advanced maturation, featuring superior sarcomeric structures, improved calcium transients, and upregulated maturation genes compared to non-piezoelectric constructs. Furthermore, these engineered piezoelectric cardiac constructs demonstrate significant structural and functional repair of infarcted myocardium, as evidenced by enhanced ejection and shortening fraction, reduced fibrosis and inflammation, and increased angiogenesis. The findings underscore the therapeutic potential of piezoelectric cardiac constructs for myocardial infarction therapy.

Piezoelectric properties and biocompatibility of barium titanate prepared via digital light processing

Barium titanate (BT) is widely studied in bone repair engineering due to its high dielectric constant, excellent ferroelectric properties, and non-toxic nature. However, one of the research focuses on the preparation of high-precision BT ceramics and enhances their limited mineralization bioactivity. BT is difficult to use for high-precision ceramic molding using Digital Light Processing (DLP) due to its high refractive index and strong ultraviolet absorption. In this manuscript, BT was doped with calcium silicate (CS) which has a refractive index close to photosensitive resin. The printing parameters of the composite ceramic scaffolds were determined to obtain a balance between printing efficiency and accuracy. Experimental results have demonstrated that within a CS doping ratio of up to 20 wt%, the scaffolds simultaneously meet the piezoelectric coefficient and mechanical properties of natural bone. Furthermore, mineralization and cell experiments have shown that the composite scaffold exhibits improved degradation rate, cell activity, and osteoinductivity. Subsequently, bone scaffolds with a doping ratio of 20 wt% were selected, which meet the requirements of natural bone and exhibit significantly enhanced biological activity. Research findings revealed that ceramic scaffolds after piezoelectric stimulation are more conducive to cell proliferation and growth compared to before stimulation.

Engineering 3D Scaffold-Free Nanoparticle-Laden Stem Cell Constructs for Piezoelectric Enhancement of Human Neural Tissue Formation and Function.

Electrical stimulation (ES) of cellular systems can be utilized for biotechnological applications and electroceuticals (bioelectric medicine). Neural cell stimulation especially has a long history in neuroscience research and is increasingly applied for clinical therapies. Application of ES via conventional electrodes requires external connectors and power sources, hindering scientific and therapeutic applications. Here engineering novel 3D scaffold-free human neural stem cell constructs with integrated piezoelectric nanoparticles for enhanced neural tissue induction and function is described. Tetragonal barium titanate (BaTi03) nanoparticles are employed as piezoelectric stimulators prepared as cytocompatible dispersions, incorporated into 3D self-organizing neural spheroids, and activated wirelessly by ultrasound. Ultrasound delivery (low frequency; 40kHz) is optimized for cell survival, and nanoparticle activation enabled ES throughout the spheroids during differentiation, tissue formation, and maturation. The resultant human neural tissues represent the first example of direct tissue loading with piezoelectric particles for ensuing 3D ultrasound-mediated piezoelectric enhancement of human neuronal induction from stem cells, including augmented neuritogenesis and synaptogenesis. It is anticipated that the platform described will facilitate advanced tissue engineering and in vitro modeling of human neural (and potentially non-neural) tissues, with modeling including tissue development and pathology, and applicable to preclinical testing and prototyping of both electroceuticals and pharmaceuticals.

P-111 Artificial Oocyte Activation (AOA) through piezoelectric stimulation post-Intracytoplasmic Sperm Injection (ICSI) for teratozoospermia patients

Abstract Study question Does employing piezoelectric stimulation on oocytes post-ICSI in teratozoospermia cases affect early embryonic development rates? Summary answer In a retrospective study, piezoelectric stimulation after ICSI showed increased fertilization rates and improved embryo quality in teratozoospermia cases. What is known already Fertilization can fail due to various factors. One of the causes of fertilization failure after ICSI is the inability to achieve oocyte activation, a process initiated by sperm-induced events. Piezoelectric stimulation, a method of artificial oocyte activation, involves applying specific electric currents post-ICSI, elevating Ca+2 levels. Studies suggest its efficacy in enhancing fertilization rates and improving embryo quality, particularly in cases of total fertilization failure and severe sperm abnormalities. However, available literature on the efficiency of electrical stimulation in cases of sperm abnormalities is limited. Study design, size, duration In this retrospective study conducted at our reproductive center between January 2023 and October 2023, we enrolled 122 patients diagnosed with male factor infertility. These patients were divided into two groups: the control group (n = 61) where piezoelectric stimulation was not employed post-ICSI, and the AOA group (n = 61) where piezoelectric stimulation was utilized after the ICSI procedure. Participants/materials, setting, methods The study assessed 2122 oocytes, with 1031 in the control and 1091 in the AOA group. Piezoelectric stimulation was administered oocytes approximately 20-30 minutes after ICSI. The quality of sperm samples was assessed based on Kruger’s strict criteria. Following ICSI, statistical analysis utilized Student’s t-test and chi-squared tests to assess the impact of piezoelectric stimulation on fertilization and embryo quality, considering p < 0.05 as significant and p < 0.001 as highly significant. Main results and the role of chance Clinical outcomes were compared between two groups. No significant differences were observed between the control group and AOA group regarding female age (29.93±4.9 vs. 29.93±5.11, p = 0.988) and male age (34.25±3.45 vs. 33.93±3.64, p = 0.628), the number of retrieved oocytes (16.90±11.04 vs. 17.89±9.3, p = 0.344), the number of metaphase II (11.02±6.8 vs.12.46±6.6, p = 0.162). However, a highly significant difference was noted in the distribution of fertilization rate (59.08% [397/672] vs. 66.84% [508/760], p = 0.002), high-quality embryos rate (day 3) (44.08% [175/397] vs. 54.33% [276/508], p = 0.002), blastocyst rate (40.05% [159/397] vs. 50% [254/508], p = 0.003) and the good blastocyst development rate (14.11% [56/397] vs. 24.41% [124/508], p = 0.0001). Cleavage rate was significantly higher in the AOA group (85.24% [433/508]) than control group (79.09% [314/397]), p = 0.01. Limitations, reasons for caution Constraints include the study’s retrospective, single-center design, and a limited sample size. Wider implications of the findings Piezoelectric stimulation demonstrates effectiveness in improving fertilization rates and embryo quality in teratozoospermia cases after ICSI. Trial registration number not applicable

Ultrasonic-responsive piezoelectric stimulation enhances sonodynamic therapy for HER2-positive breast cancer

IntroductionBreast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2 BC)poses a particularly challenging prognosis due to its heightened invasiveness and metastatic potential. The objective of this study was to construct a composite piezoelectric nanoparticle based on poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) for imaging and treatment of HER2 BC.MethodBy reshaping the crystal structure of P(VDF-TrFE) piezoelectric nanoparticles, improving hydrophilicity, and incorporating imaging capabilities, we developed piezoelectric composite nanoparticles (PGd@tNBs) that integrate imaging and therapeutic functions. The in vitro characterization encompassed the assessment of piezoelectric properties, hydrophilicity, imaging performance, and therapeutic efficacy of these particles. The targeting and therapeutic effectiveness of PGd@tNBs particles were further validated in the SK-BR3 cell line and subsequently confirmed in HER2-positive tumor-bearing mice.ResultsThe nanoparticle demonstrated excellent biocompatibility and impressive multimodal imaging performance. Magnetic resonance imaging (MRI) observations revealed significant accumulation of PGd@tNBs particles in the HER2 positive tumor, exhibiting superior contrast-enhanced ultrasound performance compared to traditional ultrasound contrast agents, and small animal in vivo imaging showed that PGd@tNBs particles were primarily excreted through respiration and urinary metabolism. Piezoforce Microscopy characterization highlighted the outstanding piezoelectric properties of PGd@tNBs particles. Upon targeted binding to HER2-BC, ultrasound stimulation influenced the cell membrane potential, leading to reversible electroporation. This, in turn, affected the balance of calcium ions inside and outside the cells and the mitochondrial membrane potential. Following ingestion by cells, PGd@tNBs, when exposed to ultrasound, triggered the generation of reactive oxygen species (ROS), resulting in the consumption of glutathione and superoxide dismutase and achieving sonodynamic therapy. Notably, repeated ultrasound stimulation, post PGd@tNBs particles binding and entry into cells, increased ROS production and elevated the apoptosis rate by approximately 45%.ConclusionIn conclusion, the PGd@tNBs particles developed exhibit outstanding imaging and therapeutic efficacy, holding potential for precise diagnosis and personalized treatment of HER2 BC.

Piezoelectric stimulation enhances bone regeneration in alveolar bone defects through metabolic reprogramming of macrophages

AbstractImmunomodulation has emerged as a promising strategy for promoting bone regeneration. However, designing osteoimmunomodulatory biomaterial that can respond to mechanical stress in the unique microenvironment of alveolar bone under continuous occlusal stress remains a significant challenge. Herein, a wireless piezoelectric stimulation system, namely, piezoelectric hydrogel incorporating BaTiO3 nanoparticles (BTO NPs), is successfully developed to generate piezoelectric potentials for modulating macrophage reprogramming. The piezoelectric stimulation reprograms macrophages towards the M2 phenotype, which subsequently induces osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RNA sequencing analysis reveals that piezoelectricity‐modulated macrophage M2 polarization is closely associated with metabolic reprogramming, including increased amino acid biosynthesis and fatty acid oxidation. The composite hydrogel with excellent biocompatibility exhibits immunomodulatory and osteoinductive activities. In a rat model of alveolar bone defects, the piezoelectric hydrogel effectively promotes endogenous bone regeneration at the load‐bearing sites. The piezoelectric‐driven osteoimmunomodulation proposed in this study not only broadens understanding of the mechanism underlying piezoelectric biomaterials for tissue regeneration but also provides new insights into the design and development of next‐generation immunomodulatory biomaterials.

Dynamic regulation of stem cell adhesion and differentiation on degradable piezoelectric poly (L-lactic acid) (PLLA) nanofibers.

Degradable piezoelectric materials possess significant potential for application in the realm of bone tissue regeneration. However, the correlation between cell regulation mechanisms and the dynamic variation caused by material degradation has not been explained, hindering the optimization of material design and its in vivo application. Herein, piezoelectric poly (L-lactic acid) (PLLA) nanofibers with different molecular weights (MW) were fabricated, and the effects of their piezoelectric properties, structural morphology, and material products during degradation on the adhesion and osteogenic differentiation of mesenchymal stem cells (MSCs) were investigated. Our results demonstrated that cell adhesion-mediated piezoelectric stimulation could significantly enhance cell spreading, cell orientation, and upregulate the expression of calmodulin, which further triggers downstream signaling cascade to regulate osteogenic differentiation markers of type I collagen and runt-related transcription factor 2. Additionally, during the degradation of the nanofibers, the piezoelectric properties of PLLA weakened, the fibrous structure gradually diminished, and pH levels in the vicinity decreased, which resulting in reduced osteogenic differentiation capability of MSCs. However, nanofibers with higher MW (280kDa) have the ability to maintain the fibrous morphology and piezoelectricity for a longer time, which can regulate the osteogenic differentiation of stem cells for more than 4 weeks. These findings have provide a new insight to correlate cell behavior with MW and the biodegradability of piezopolymers, which revealed an active method for cell regulation through material optimization for bone tissue engineering in near future.

Osteo-inductive effect of piezoelectric stimulation from the poly(l-lactic acid) scaffolds.

Piezoelectric biomaterials can generate piezoelectrical charges in response to mechanical activation. These generated charges can directly stimulate bone regeneration by triggering signaling pathway that is important for regulating osteogenesis of cells seeded on the materials. On the other hand, mechanical forces applied to the biomaterials play an important role in bone regeneration through the process called mechanotransduction. While mechanical force and electrical charges are both important contributing factors to bone tissue regeneration, they operate through different underlying mechanisms. The utilizations of piezoelectric biomaterials have been explored to serve as self-charged scaffolds which can promote stem cell differentiation and the formation of functional bone tissues. However, it is still not clear how mechanical activation and electrical charge act together on such a scaffold and which factors play more important role in the piezoelectric stimulation to induce osteogenesis. In our study, we found Poly(l-lactic acid) (PLLA)-based piezoelectric scaffolds with higher piezoelectric charges had a more pronounced osteoinductive effect than those with lower charges. This provided a new mechanistic insight that the observed osteoinductive effect of the piezoelectric PLLA scaffolds is likely due to the piezoelectric stimulation they provide, rather than mechanical stimulation alone. Our findings provide a crucial guide for the optimization of piezoelectric material design and usage.

A coaxial electrospun mat coupled with piezoelectric stimulation and atorvastatin for rapid vascularized bone regeneration.

The repair of critical bone defects caused by various clinical conditions needs to be addressed urgently, and the regeneration of large bone defects depends on early vascularization. Therefore, enhanced vascularization of artificial bone grafts may be a promising strategy for the regeneration of critical-sized bone defects. Taking into account the importance of rapid angiogenesis during bone repair and the potential of piezoelectric stimulation in promoting bone regeneration, novel coaxial electrospun mats coupled with piezoelectric materials and angiogenic drugs were fabricated in this study using coaxial electrospinning technology, with a shell layer loaded with atorvastatin (AVT) and a core layer loaded with zinc oxide (ZnO). AVT was used as an angiogenesis inducer, and piezoelectric stimulation generated by the zinc oxide was used as an osteogenesis enhancer. The multifunctional mats were characterized in terms of morphology, core-shell structure, piezoelectric properties, drug release, and mechanical properties, and their osteogenic and angiogenic capabilities were validated in vivo and ex vivo. The results revealed that the coaxial electrospun mats exhibit a porous surface morphology and nanofibers with a core-shell structure, and the piezoelectricity of the mats improved with increasing ZnO content. Excellent biocompatibility, hydrophilicity and cell adhesion were observed in the multifunctional mats. Early and rapid release of AVT in the fibrous shell layer of the mat promoted angiogenesis in human umbilical vascular endothelial cells (HUVECs), whereas ZnO in the fibrous core layer harvested bioenergy and converted it into electrical energy to enhance osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs), and both modalities synergistically promoted osteogenesis and angiogenesis. Furthermore, optimal bone regeneration was achieved in a model of critical bone defects in the rat mandible. This osteogenesis-promoting effect was induced by electrical stimulation via activation of the calcium signaling pathway. This multifunctional mat coupling piezoelectric stimulation and atorvastatin promotes angiogenesis and bone regeneration, and shows great potential in the treatment of large bone defects.

Development and evaluation of 3D composite scaffolds with piezoelectricity and biofactor synergy for enhanced articular cartilage regeneration.

The inability of articular cartilage to self-repair following injuries frequently precipitates osteoarthritis, profoundly affecting patients' quality of life. Given the limitations inherent in current clinical interventions, an urgent need exists for more effective cartilage regeneration methodologies. Previous studies have underscored the potential of electrical stimulation in cartilage repair, thus motivating the investigation of innovative strategies. The present study introduces a three-dimensional scaffold fabricated through a composite technique that leverages the synergy between piezoelectricity and biofactors to enhance cartilage repair. This scaffold is composed of polylactic acid (PLLA) and barium titanate (BT) for piezoelectric stimulation and at the bottom with a collagen-coated layer infused with fibroblast growth factor-18 (FGF-18) for biofactor delivery. Designed to emulate the properties of natural cartilage, the scaffold enables controlled generation of piezoelectric charges and the sustained release of biofactors. In vitro tests confirm that the scaffold promotes chondrocyte proliferation, matrix hyperplasia, cellular migration, and the expression of genes associated with cartilage formation. Moreover, in vivo studies on rabbits have illustrated its efficacy in catalyzing the in situ regeneration of articular cartilage defects and remodeling the extracellular matrix. This innovative approach offers significant potential for enhancing cartilage repair and holds profound implications for regenerative medicine.

Self-generating electricity system driven by aqueous humor flow and trabecular meshwork contraction motion activated BCKa for glaucoma intraocular pressure treatment.

Primary open-angle glaucoma (POAG) is the most common form of glaucoma and the leading cause of irreversible vision loss and blindness worldwide. Intraocular pressure (IOP) is the only modifiable risk factor, and prompt treatment to lower IOP can effectively slow the rate of vision loss due to glaucoma. Trabecular meshwork (TM) cells can maintain IOP homeostasis by correcting and adjusting the resistance to aqueous humor outflow in response to sustained pressure changes. TM cells' function is reduced, and membrane ion channels are impaired in POAG. The dysfunction of Large conductance Ca2+-activated K+ (BKCa) plays a central role in the pathogenesis of POAG. In this work, we targeted MXene nanoparticles (MXene-RGD) with piezoelectric response to TM cells in a 3D model of glaucoma in vitro as well as in the rabbit Transient Ocular Hypertension (OHT) Model in vivo. MXene-RGD gives the TM electromechanical transfer properties, while the self-enhancing and self-generated electricity properties of the TM are determined by the aqueous humor flow rate and the size of the deformation of the TM. MXene-RGD is nontoxic, as illustrated by a cell toxicity study and histological examination. In a 3D in vitro model of high-pressure glaucoma, whole-cell patch-clamp confirmed that piezoelectric stimulation turns on BKCa, which reduces the volume of the cell. MXene-RGD was injected into the anterior chamber with minimal trauma, i.e., anterior chamber injection, and specifically targeted to TM cells. The OHT model in vivo confirmed the potential IOP-lowering ability of MXene-RGD. We evaluated the ion channels involved in the reduction of IOP by MXene-RGD by pre-treatment with a BKCa channel blocker (iberiotoxin, IbTX) and a voltage-gated Ca2+channel blocker (nifedipine). Quantitative qPCR analysis showed that MXene-RGD inhibited the upregulation of mRNA expression levels of the myofibroblast marker α-smooth muscle actin (α-SMA) and the inflammatory response marker interleukin-6 (IL-6) induced by IOP. Histology confirmed that MXene-RGD attenuated IOP-induced proliferation and collagen production in the TM. Taken together, we present for the first time a minimally invasive surgical approach for targeting TM cells for POAG by utilizing piezoresponse nanomaterials to target BKCa to repair or awaken the ability of TM cells to regulate IOP homeostasis on their own.

The marriage of immunomodulatory, angiogenic, and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scaffold for military medicine

BackgroundMost bone-related injuries to grassroots troops are caused by training or accidental injuries. To establish preventive measures to reduce all kinds of trauma and improve the combat effectiveness of grassroots troops, it is imperative to develop new strategies and scaffolds to promote bone regeneration.MethodsIn this study, a porous piezoelectric hydrogel bone scaffold was fabricated by incorporating polydopamine (PDA)-modified ceramic hydroxyapatite (PDA-hydroxyapatite, PHA) and PDA-modified barium titanate (PDA-BaTiO3, PBT) nanoparticles into a chitosan/gelatin (Cs/Gel) matrix. The physical and chemical properties of the Cs/Gel/PHA scaffold with 0–10 wt% PBT were analyzed. Cell and animal experiments were performed to characterize the immunomodulatory, angiogenic, and osteogenic capabilities of the piezoelectric hydrogel scaffold in vitro and in vivo.ResultsThe incorporation of BaTiO3 into the scaffold improved its mechanical properties and increased self-generated electricity. Due to their endogenous piezoelectric stimulation and bioactive constituents, the as-prepared Cs/Gel/PHA/PBT hydrogels exhibited cytocompatibility as well as immunomodulatory, angiogenic, and osteogenic capabilities; they not only effectively induced macrophage polarization to M2 phenotype but also promoted the migration, tube formation, and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) and facilitated the migration, osteo-differentiation, and extracellular matrix (ECM) mineralization of MC3T3-E1 cells. The in vivo evaluations showed that these piezoelectric hydrogels with versatile capabilities significantly facilitated new bone formation in a rat large-sized cranial injury model. The underlying molecular mechanism can be partly attributed to the immunomodulation of the Cs/Gel/PHA/PBT hydrogels as shown via transcriptome sequencing analysis, and the PI3K/Akt signaling axis plays an important role in regulating macrophage M2 polarization.ConclusionThe piezoelectric Cs/Gel/PHA/PBT hydrogels developed here with favorable immunomodulation, angiogenesis, and osteogenesis functions may be used as a substitute in periosteum injuries, thereby offering the novel strategy of applying piezoelectric stimulation in bone tissue engineering for the enhancement of combat effectiveness in grassroots troops.

Electrospun Piezoelectric Scaffold with External Mechanical Stimulation for Promoting Regeneration of Peripheral Nerve Injury.

Safe and efficient provision of electrical stimulation (ES) for nerve repair and regeneration is a problem that needs to be addressed. In this study, a silk fibroin/poly(vinylidene fluoride-co-hexafluoropropylene)/Ti3C2Tx (SF/PVDF-HFP/MXene) composite scaffold with piezoelectricity was developed by electrospinning technology. MXene was loaded to the scaffold to enhance the piezoelectric properties (Output voltage reaches up to 100 mV), mechanical properties, and antibacterial activity. Cell experiments demonstrated piezoelectric stimulation under external ultrasonication for promoting the growth and proliferation of Schwann cells (SCs) cultured on this electrospun scaffold. Further in vivo study with rat sciatic nerve injury model revealed that the SF/PVDF-HFP/MXene nerve conduit could induce the proliferation of SCs, enhance the elongation of axon, and promote axonal myelination. Under the piezoelectric effect of this nerve scaffold, the rats with regenerative nerve exhibited a favorable recovery effect of motor and sensory function, indicating a safe and feasible method of using this SF/PVDF-HFP/MXene piezoelectric scaffold for ES provision in vivo.

Ultrasound-driven BaTiO 3 nanorobots patching immunologic barrier to cure chronic rheumatoid arthritis

The disruption and reconstruction of the TREM2⁺ tissue resident macrophage (TRM) barrier on the surface of synovial lining play a key role in the activation and "remission" of rheumatoid arthritis (RA), which engender the prediction of this immunologic barrier as a potential driver for the achievement of "cure" in RA. However, strategies to promote the reconstruction of this barrier have not been reported, and the effect of patching this barrier remains unidentified. On the other hand, appropriate piezoelectric stimulation can reprogram macrophages, which has never been exerted on this barrier TRM yet. Herein, we design piezoelectric tetragonal BaTiO₃ (BTO) ultrasound-driven nanorobots (USNRs) by the solvothermal synthesis method, which demonstrates satisfactory electro-mechanical conversion effects, paving the way to generate controllable electrical stimulation under ultrasound to reprogram the barrier TRM by minimally invasive injection into joint cavity. It is demonstrated that the immunologic barrier could be patched by this USNR effectively, thereby eliminating the hyperplasia of vessels and nerves (HVN) and synovitis. Additionally, TREM2 deficiency serum-transfected arthritis (STA) mice models are applied and proved the indispensable role of TREM2 in RA curing mediated by USNR. In all, our work is an interesting and important exploration to expand the classical tetragonal BTO nanoparticles in the treatment of autoimmune diseases, providing a new idea and direction for the biomedical application of piezoelectric ceramics.

Poly(l‐Lactic Acid) Nanofiber‐Based Multilayer Film for the Electrical Stimulation of Nerve Cells

AbstractPoly(l‐lactic acid) (PLLA) films have excellent piezoelectric properties, but the strong hydrophobicity of the surface makes it difficult for cells to attach there. PLLA nanofibers have good biocompatibility, but the weak piezoelectric coefficient limits the ability of the nanofibers to stimulate cell growth. Therefore, the PLLA piezoelectric film is combined with the PLLA nanofibers to make a multilayer film. In our tests, the piezoelectric output of the multilayer film ≈260 mV. In the biological experiments section, without piezoelectric stimulation, the cell length on the nanofibers is approximately twice that of the cells in the blank control group. The length of cells cultured on piezoelectric‐based stimulated nanofibers is more than twice that of cells cultured on nanofibers without piezoelectric stimulation. Therefore, it is confirmed that under the dual action of nanofiber guidance and piezoelectric stimulation, the growth rate of cells is four times faster than that in ordinary Petri dishes. Intracellular calcium imaging experiments confirmed that the concentration of Ca2+ in electrically stimulated cells is approximately twice that of ordinary cells. It is also confirmed that piezoelectric materials can complete electrical stimulation of cells in indirect contact with cells.

Bioinspired Piezoelectric Periosteum to Augment Bone Regeneration via Synergistic Immunomodulation and Osteogenesis.

Ideal periosteum materials are required to participate in a sequence of bone repair-related physiological events, including the initial immune response, endogenous stem cell recruitment, angiogenesis, and osteogenesis. However, conventional tissue-engineered periosteal materials have difficulty achieving these functions by simply mimicking the periosteum via structural design or by loading exogenous stem cells, cytokines, or growth factors. Herein, we present a novel biomimetic periosteum preparation strategy to comprehensively enhance the bone regeneration effect using functionalized piezoelectric materials. The resulting biomimetic periosteum possessing an excellent piezoelectric effect and improved physicochemical properties was prepared using a biocompatible and biodegradable poly(3-hydroxybutyric acid-co-3-hydrovaleric acid) (PHBV) polymer matrix, antioxidized polydopamine-modified hydroxyapatite (PHA), and barium titanate (PBT), which were further incorporated into the polymer matrix to fabricate a multifunctional piezoelectric periosteum by a simple one-step spin-coating method. The addition of PHA and PBT dramatically enhanced the physicochemical properties and biological functions of the piezoelectric periosteum, resulting in improved surface hydrophilicity and roughness, enhanced mechanical performance, tunable degradation behavior, and stable and desired endogenous electrical stimulations, which is conducive to accelerating bone regeneration. Benefiting from endogenous piezoelectric stimulation and bioactive components, the as-fabricated biomimetic periosteum demonstrated favorable biocompatibility, osteogenic activity, and immunomodulatory functions in vitro, which not only promoted adhesion, proliferation, and spreading as well as osteogenesis of mesenchymal stem cells (MSCs) but also effectively induced M2 macrophage polarization, thereby suppressing reactive oxygen species (ROS)-induced inflammatory reactions. Through in vivo experiments, the biomimetic periosteum with endogenous piezoelectric stimulation synergistically accelerated the formation of new bone in a rat critical-sized cranial defect model. The whole defect was almost completely covered by new bone at 8 weeks post treatment, with a thickness close to that of the host bone. Collectively, with its favorable immunomodulatory and osteogenic properties, the biomimetic periosteum developed here represents a novel method to rapidly regenerate bone tissue using piezoelectric stimulation.

Biomineralized Piezoelectrically Active Scaffolds for Inducing Osteogenic Differentiation.

There is an endogenous electric field in living organisms, which plays a vital role in the development and regeneration of bone tissue. Therefore, self-powered piezoelectric material for bone repair has become hot research in recent years. However, the current piezoelectric materials for tissue regeneration still have the shortcomings of lack of biological activity and three-dimensional structure. Here, we proposed a three-dimensional polyurethane foam (PUF) scaffold coated with piezoelectric poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and modified by a calcium phosphate (CaP) mineralized coating. The preferred scaffold has an open circuit voltage and short circuit current output of 5 V and 200 nA. Combining the physical and chemical properties of the CaP coating, the piezoelectric signal of PVDF-HFP and the three-dimensional structure of PUF, the scaffold exhibits superior promotion of cell osteogenic differentiation and ectopic bone formation in vivo. The mechanism is attributed to an increase in intracellular Ca2+ levels in response to chemical and piezoelectric stimulation with the material. This research not only paves the way for the application of piezoelectric scaffolds to stimulate osteoblasts differentiation in situ, but also lays the foundation for the clinical treatment of long-term osteoporosis.